Major depressive disorder (MDD) is a mood disorder majorly responsible for disability and mortality worldwide. With a lifetime prevalence of 15-20%, it is the main cause of functional impairment in Western societies as well as the fourth most debilitating illness in the world. Although the pathophysiology of MDD is not yet fully understood, some evidence that suggest the presence of a neuroanatomical deficiency have given rise to the theory of a specific imbalance in the monoamine neurotransmitters noradrenaline (NA) and/or serotonin (5-HT) levels in the brain. Overall, the various classes of antidepressant agents that have been developed to increase monoamine levels on the basis of this proposal have been successful. However, facts relating to prevalent escalation in the illness and recurring episodes of depression point towards a need to enhance clinical treatment. Most conventional antidepressants such as selective serotonin reuptake inhibitors (SSRI) and selective serotonin and noradrenaline inhibitors (SNRI) pose problems in symptomatic improvement. These include therapeutic lag, safety and tolerability issues, making more than 30% patients with MDD unable to reach adequate relief. In this respect, the action mechanism has moved beyond conventional SSRI and lead to the introduction of vilazodone, a novel antidepressant with an additional 5-HT1A partial agonist profile argued to be of potential benefit for a greater efficacy, faster onset of action and better tolerability. Using secondary data, this project aimed to evaluate the role of vilazodone as a SPARI-drug in the overall clinical treatment of MDD as well as its potential in addressing some of the most common obstacles in antidepressant treatment. Study results proved vilazodone’s efficacy to be superior to placebo. Patients across all studies showed significant improvement in depressive symptoms measured in MADRS and HAMD17. Vilazodone was also shown to be generally safe and tolerable but was not positively distinguished from placebo with regards to adverse effects. An overall, meaningful improvement in depressive symptoms was demonstrated in vilazodone, which reinforces its merit as an important treatment option for patients with MDD.

Irritable bowel syndrome (IBS) is a functional disorder that affects the gastrointestinal tract and especially the large intestine. The pathogenesis of the disease is not fully understood, for that reason there is still no cure and current therapy focuses on symptom relief. The disease manifests itself in the form of abdominal pain, bloating, constipation or diarrhoea. New studies have shown a link between IBS and communication between the central nervous system and the gut. Serotonin and norepinephrine seem to be important for the course of the disease. The purpose of this literature review was to study the efficacy and safety of certain antidepressant preparations belonging to tricyclic antidepressants and selective serotonin reuptake inhibitors in the treatment of IBS. This work focused on the effect of preparations and how tolerable they are with respect to their side effects. Articles presented in this work were found in the PubMed database with the keywords "irritable bowel syndrome", "serotonin reuptake inhibitor", " tricyclic antidepressants ". Amitriptyline 10 mg and imipramine 25 mg provided a statistically significant symptom relief in IBS with diarrhoea (IBS-D) compared to placebo. In addition, tianeptine 12.5 mg 3 times / day, which belongs to the selective serotonin reuptake enhancer (SSRE) group, gave a corresponding symptom relief as amitriptyline 10 mg once / day. The difference between the two was not statistically significant, but the study was open label and non-placebo-controlled, which made it difficult to draw any conclusions. Fluoxetine, which belongs to the selective serotonin reuptake inhibitor (SSRI) group, produced a statistically significant effect compared to placebo in the treatment of constipation IBS (IBS-C). In contrast, paroxetine-CR did not have any statistically significant effect on abdominal pain in IBS-C compared with placebo. However, more patients in the paroxetine group achieved the secondary outcome (clinical global improvement) with scores of 1-2 on the scale Clinical Global Impressions-Improvement (CGI-I). Based on the studies presented in this literature study, it is concluded that a low dose of TCA is an effective and safe treatment for IBS-D while SSRIs are effective and safe in the treatment of IBS-C compared to placebo. / Irritable bowel syndrome (IBS), är funktionella störningar som drabbar gastrointestinalkanalen och framför allt kolon. Patogenesen till sjukdomen är inte helt klarlagd, av den anledningen saknas fortfarande någon botande behandling och dagens terapi fokuserar på symtomlindring. Sjukdomen yttrar sig i form av buksmärta, uppblåsthet, förstoppning eller diarré. Senaste studier har visat en koppling mellan IBS och kommunikation mellan centrala nervsystemet och tarmen. Serotonin och noradrenalin verkar ha betydelse för sjukdomsförlopp. Syftet med detta litteraturarbete var att studera effektivitet och säkerhet för några antidepressiva preparat som tillhör tricykliska antidepressiva och selektiva serotonin återupptagshämmare vid behandling av IBS. Detta arbete fokuserade på effekten av preparaten och hur tolererbara de är med avseende på deras biverkningar. Artiklar som presenteras i detta arbete söktes i databasen Pubmed med sökord ”irritable bowel syndrome”, ”serotonin reuptake inhibitors”, ” tricyclic antidepressants”. Amitriptylin 10mg och imipramin 25mg gav en statistiskt signifikant symtomlindring vid IBS med diarré (IBS-D) jämfört med placebo. Dessutom gav tianeptin 12,5mg 3 gånger/dag, som tillhör läkemedelsgruppen selektiv serotonin återupptagsenhancer (SSRE), en likvärdig symtomlindring som amitriptylin 10mg en gång/dag. Skillnaden mellan de två var inte statistiskt signifikant, däremot var studien openlabel och icke-placebokontrollerad vilket gör det svårt att dra någon slutsats. Fluoxetin, som tillhör läkemedelsgruppen selektiva serotonin återupptagshämmare SSRI, gav en statistiskt signifikant effekt jämfört med placebo vid behandling av IBS med förstoppning (IBS-C). Däremot gav paroxetin-CR ingen statistiskt signifikant effekt på buksmärta vid IBS-C jämfört med placebo, dock uppnådde fler i paroxetingruppen den sekundära utfallsvariabeln (global klinisk förbättring) och fick poäng mellan 1 – 2 på skalan Clinical Global Impressions-Improvement (CGI-I).  Baserat på studierna som presenteras i denna litteraturstudie dras slutsatsen att en låg dos TCA är en effektiv och säker behandling vid IBS-D medan SSRI är effektiva och säkra vid behandling av IBS-C jämfört med placebo.

This study examined the relationship between selective serotonin reuptake inhibitor (SSRI) medication and auditory measures in clinically depressed women. Experimental subjects were tested in both a medicated and unmedicated condition. Experimental subjects were compared to a normal control group; additionally intrasubject comparison was made within the experimental group. Test measures included: audiometry, tympanometry, otoacoustic emissions, uncomfortable loudness level, masking level difference, SCAN-A, Synthetic Sentence Identification (SSI), and the low predictability section of the Revised Speech in noise (RSPIN). The unmedicated group scored significantly less favorably than the control group on the following tests; SCAN-A (composite, filtered words, and auditory figure ground), R-SPIN (0MCR condition in both the right and left ears). Additionally, the unmedicated group scored significantly less favorably than the medicated group on the SSI (-20MCR condition right ear only) and of the R-SPIN (0MCR condition right ear only). Other test measures indicated consistent trends but did reach significance.

Psychotropic drugs are commonly used group of pharmaceuticals, their main effect is to alter psychic condition, including mental diseases treatment. Symptoms of mental illnesses are more and more common, theref orenumber of patients diagnosed with mental illnes, and thus using psychotropics, is growing stronger. But using psychotropics during gestation is not without risks for mother and embryo itself. However, thanks to the absence of controlled human studies, the knowledge of emrbyotoxic effects of pschotropics is limited to casuistics, reported side effects and animal experimental studies. Many of those studies suggests emrbyotoxic potential of psychotropic drugs, on the other hand, others claim their safety. The goal of this thesis is to test at least some of them, using CHEST method, that allows us to observe direct effect of unmetabolized substance on chick embryo. In this thesis we tested selected psychotropics, very common antidepressant fluoxetine (prozac) and antipsychotic drug olanzapine, for embryotoxicity, using in ovo method CHEST with chick embryos as model organism. By bypassing the maternal organism and his metabolism, this method allows to observe direct effect of unmetabolized substance on chick embryo. Results revealed embryotoxic effect of fluoxetin in dosage 10-2 and 10-3 on 3rd and...

Worldwide, pharmaceutical compounds continue to increase in our aquatic environment. The predominant route into nature is through wastewater treatment plants since the elimination of residual pharmaceuticals is still not mainstream in WWTPs. Fluoxetine is an antidepressant which is commonly prescribed to treat human depression. Wastewater residual fluoxetine is typically found in waters around the world, and can thus affect exposed organisms, such as fish and invertebrates. However, how fluoxetine may affect mating behaviour in exposed organisms remains poorly understood, and particularly so in invertebrates. This is hampering our understanding of the consequences of our medicine leaking into nature because mating behaviour often affects fitness, and invertebrates are key organisms in food chains. Therefore, I here experimentally investigated long-term effects of environmental relevant concentration of fluoxetine (20 ng L-1) on mating behaviours of male and female freshwater isopod Asellus aquaticus. I demonstrate that fluoxetine reduced male mating attempts with receptive females. Further, there was a tendency for fluoxetine exposure to increase latency to form pre-copula. There was no effect of fluoxetine exposure on male latency to encounter females or female responses toward males. These results indicate that fluoxetine also can affect isopods by reducing mating behaviour. In the long-term, if reproduction is delayed or reduced, it may cause a reduction in populations and thus, alter the whole ecosystem.

Danos mitocondriais e diminuição nos níveis de ATP têm sido recentemente atribuídos à sertralina. Nós investigamos o efeito da sertralina em plaquetas humanas, já que estas células demonstram várias similaridades funcionais com neurônios e astrócitos. Os efeitos da sertralina em diferentes parâmetros foram investigados em plaquetas lavadas de 18 voluntários saudáveis do sexo masculino, depois de 24h de exposição ao fármaco. A toxicidade da sertralina foi observada apenas nas concentrações mais altas, 30 e 100μM, nas quais a viabilidade das plaquetas foi significantemente reduzida a 76 ± 3% e 20 ± 2 %, respectivamente. As mesmas concentrações reduziram o ATP a 73 ± 3% e 13 ± 2 %, respectivamente. Os valores basais de glicogênio não foram afetados significativamente pelo tratamento com sertralina. A captação de glutamato foi reduzida de forma significativa após o tratamento com 3, 30 e 100 μM, em 28 ± 6 %, 32 ± 5% e 54 ± 4 %, respectivamente. Nosso estudo demonstra que a sertralina em concentrações terapêuticas não compromete a viabilidade plaquetária, porém seu uso não pode ser considerado isento de risco, pois em um cenário no qual os níveis de glutamato extracelular estão potencialmente aumentados, a sertralina poderia agravar uma condição excitotóxica / Mitochondrial damage and fall in ATP levels have been recently attributed to sertraline. We investigated the effect of sertraline on human platelets, since these cells display several functional similarities with neurons and astrocytes. The effects of sertraline on different parameters were investigated in washed platelets from 18 healthy male volunteers, after 24 h of drug exposure. Sertraline toxicity was observed only at the highest concentrations, 30 and 100 μM, which significantly reduced platelet viability to 76 ± 3% and 20 ± 2%, respectively. The same concentrations significantly decreased total ATP to 73 ± 3% and 13 ± 2%, respectively. Basal values of glycogen were not significantly affected by sertraline treatment. The glutamate uptake was significantly reduced after treatment with 3, 30 and 100 μM, by 28 ± 6%, 32 ± 5% and 54 ± 4%, respectively. Our study showed that sertraline at therapeutic concentrations does not compromise platelet viability, but its use may not be without risk, since in a scenario where extracellular glutamate levels are potentially increased, sertraline might aggravate an excitotoxic condition.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Background: Functional imaging studies have examined the neural circuitry of subjects with obsessive compulsive disorder (OCD), and the changes associated with oral treatment. However, the effect of intravenous (IV) serotonin reuptake inhibitors (SRIs) on neuronal activation has not been investigated in OCD subjects, even though IV SRIs have been shown to be more effective than oral pharmacotherapy. Methods: Six OCD and 6 control subjects underwent functional magnetic resonance imaging while receiving infusions of citalopram and placebo, in a randomized, crossover design. Results: Compared to controls, OCD subjects exhibited hyperactivation of the orbitofrontal cortex and anterior cingulate cortex while looking at symptom provoking pictures at baseline. However, after the citalopram infusion, patients displayed attenuations of these regions, which correlated with reductions in subjective anxiety ratings. Conclusion: The effects observed after the IV citalopram infusion are similar to modulations observed after prolonged oral pharmacotherapy trials, illustrating the benefits of IV SRIs.

Background: Functional imaging studies have examined the neural circuitry of subjects with obsessive compulsive disorder (OCD), and the changes associated with oral treatment. However, the effect of intravenous (IV) serotonin reuptake inhibitors (SRIs) on neuronal activation has not been investigated in OCD subjects, even though IV SRIs have been shown to be more effective than oral pharmacotherapy. Methods: Six OCD and 6 control subjects underwent functional magnetic resonance imaging while receiving infusions of citalopram and placebo, in a randomized, crossover design. Results: Compared to controls, OCD subjects exhibited hyperactivation of the orbitofrontal cortex and anterior cingulate cortex while looking at symptom provoking pictures at baseline. However, after the citalopram infusion, patients displayed attenuations of these regions, which correlated with reductions in subjective anxiety ratings. Conclusion: The effects observed after the IV citalopram infusion are similar to modulations observed after prolonged oral pharmacotherapy trials, illustrating the benefits of IV SRIs.

During pregnancy, 4 - 7% of women suffer from major depressive disorder. When antidepressive treatment is needed, selective serotonin reuptake inhibitors (SSRIs) are the most commonly used. Although severe complications from SSRI treatment are rare, association with a number of adverse pregnancy and fetal outcomes has been found. Also, antenatal depression per se has been shown to affect pregnancy outcomes. The overall aim of this thesis was to examine the effects of SSRIs on human placenta and embryo. In the first study, gene expression was investigated in placenta from depressed, SSRI-treated and healthy pregnant women, using microarray analysis. Antenatal depression and SSRI treatment induced alterations in gene expression, but only 20 genes in common were noted. Validation with qRT-PCR showed that six out of seven selected genes were altered in SSRI-treated women compared with controls, and two genes were altered between depressed women and controls. In study two, the protein levels in placenta from depressed, SSRI-treated and healthy pregnant women were investigated, focusing on the NGF signaling pathway. NGF, phosphorylated Raf-1, ROCK2 and phosphorylated ROCK2, were altered in both SSRI-treated and depressed women, although the proteins were regulated differently in the two groups. In the third study, human embryos were treated with fluoxetine. Embryo development and protein expression were studied. Fluoxetine had some effect on the timing of embryo developmental stages. Also, several proteins were uniquely found in fluoxetine-treated embryos compared with untreated embryos. Fluoxetine also altered the levels of proteins secreted from the embryo. In the fourth study, the human neuroblastoma cell line SH-SY5Y/TrkA was treated with TPA and NGF. The activation of Raf-1 was investigated and the involvement of Ras and PKC was studied. Both NGF and TPA activated Raf-1, but to a different extent and via different pathways. The NGF-induced activation of Raf-1 was mediated via Ras, while TPA induced signaling via PKC. In conclusion, SSRI treatment and antenatal depression influence placental gene and protein expression. These findings may affect placental development and function, which in turn could affect fetal development. Also, direct exposure of embryos to fluoxetine has some effects on embryo development and protein expression, which may affect the development of the fetus.